National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21731-6. doi: 10.1073/pnas.1012153107. Epub 2010 Nov 22.
Nucleotide variations, including SNPs, in the coding regions of disease genes are important targets for RNAi treatment, which is a promising medical treatment for intractable diseases such as triplet repeat diseases. However, the identification of such nucleotide variations and the design of siRNAs conferring disease allele-specific RNAi are quite difficult. In this study we developed a pull-down method to rapidly identify coding SNP (cSNP) haplotypes of triple repeat, disease-causing alleles, and we demonstrated disease allele-specific RNAi that targeted cSNP sites in mutant Huntingtin alleles, each of which possessed a different cSNP haplotype. Therefore, the methods presented here allow for allele-specific RNAi knockdown against disease-causing alleles by using siRNAs specific to disease-linked cSNP haplotypes, and advanced progress toward tailor-made RNAi treatments for triplet repeat diseases.
核苷酸变异，包括编码区域的单核苷酸多态性 (SNPs)，是 RNAi 治疗的重要靶点，RNAi 治疗是治疗三核苷酸重复疾病等难治性疾病的一种有前途的医疗方法。然而，这种核苷酸变异的鉴定和设计赋予疾病等位基因特异性 RNAi 的 siRNAs 是相当困难的。在这项研究中，我们开发了一种下拉法来快速鉴定三核苷酸重复、致病等位基因的编码 SNP (cSNP) 单倍型，我们证明了针对突变亨廷顿等位基因中 cSNP 位点的疾病等位基因特异性 RNAi，每个突变等位基因都具有不同的 cSNP 单倍型。因此，这里提出的方法允许使用针对疾病相关 cSNP 单倍型的 siRNAs 对致病等位基因进行特异性 RNAi 敲低，并朝着针对三核苷酸重复疾病的定制 RNAi 治疗取得了先进的进展。
